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The Science of the Total Environment Aug 2021Antimicrobial resistance (AMR) is a growing threat to human and animal health. Progress in molecular biology has revealed new and significant challenges for AMR... (Review)
Review
Antimicrobial resistance (AMR) is a growing threat to human and animal health. Progress in molecular biology has revealed new and significant challenges for AMR mitigation given the immense diversity of antibiotic resistance genes (ARGs), the complexity of ARG transfer, and the broad range of omnipresent factors contributing to AMR. Municipal, hospital and abattoir wastewater are collected and treated in wastewater treatment plants (WWTPs), where the presence of diverse selection pressures together with a highly concentrated consortium of pathogenic/commensal microbes create favourable conditions for the transfer of ARGs and proliferation of antibiotic resistant bacteria (ARB). The rapid emergence of antibiotic resistant pathogens of clinical and veterinary significance over the past 80 years has re-defined the role of WWTPs as a focal point in the fight against AMR. By reviewing the occurrence of ARGs in wastewater and sludge and the current technologies used to quantify ARGs and identify ARB, this paper provides a research roadmap to address existing challenges in AMR control via wastewater treatment. Wastewater treatment is a double-edged sword that can act as either a pathway for AMR spread or as a barrier to reduce the environmental release of anthropogenic AMR. State of the art ARB identification technologies, such as metagenomic sequencing and fluorescence-activated cell sorting, have enriched ARG/ARB databases, unveiled keystone species in AMR networks, and improved the resolution of AMR dissemination models. Data and information provided in this review highlight significant knowledge gaps. These include inconsistencies in ARG reporting units, lack of ARG/ARB monitoring surrogates, lack of a standardised protocol for determining ARG removal via wastewater treatments, and the inability to support appropriate risk assessment. This is due to a lack of standard monitoring targets and agreed threshold values, and paucity of information on the ARG-pathogen host relationship and risk management. These research gaps need to be addressed and research findings need to be transformed into practical guidance for WWTP operators to enable effective progress towards mitigating the evolution and spread of AMR.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Genes, Bacterial; Humans; Wastewater
PubMed: 33866168
DOI: 10.1016/j.scitotenv.2021.146964 -
ACS Nano Sep 2023Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that...
Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood-brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.
Topics: Animals; Mice; Glioblastoma; CRISPR-Cas Systems; RNA, Guide, CRISPR-Cas Systems; Glioma; Extracellular Vesicles; Glutathione
PubMed: 37646615
DOI: 10.1021/acsnano.2c12857 -
Frontiers in Cellular and Infection... 2020HIV Tat protein is a critical protein that plays multiple roles in HIV pathogenesis. While its role as the transactivator of HIV transcription is well-established, other... (Review)
Review
HIV Tat protein is a critical protein that plays multiple roles in HIV pathogenesis. While its role as the transactivator of HIV transcription is well-established, other non-viral replication-associated functions have been described in several HIV-comorbidities even in the current antiretroviral therapy (ART) era. HIV Tat protein is produced and released into the extracellular space from cells with active HIV replication or from latently HIV-infected cells into neighboring uninfected cells even in the absence of active HIV replication and viral production due to effective ART. Neighboring uninfected and HIV-infected cells can take up the released Tat resulting in the upregulation of inflammatory genes and activation of pathways that leads to cytotoxicity observed in several comorbidities such as HIV associated neurocognitive disorder (HAND), HIV associated cardiovascular impairment, and accelerated aging. Thus, understanding how Tat modulates host and viral response is important in designing novel therapeutic approaches to target the chronic inflammatory effects of soluble viral proteins in HIV infection.
Topics: HIV Infections; HIV-1; Humans; tat Gene Products, Human Immunodeficiency Virus
PubMed: 32158701
DOI: 10.3389/fcimb.2020.00061 -
Frontiers in Microbiology 2016Despite its small genome size, the Human Immunodeficiency Virus 1 (HIV-1) is one of the most successful pathogens and has infected more than 70 million people worldwide... (Review)
Review
Despite its small genome size, the Human Immunodeficiency Virus 1 (HIV-1) is one of the most successful pathogens and has infected more than 70 million people worldwide within the last decades. In total, HIV-1 expresses 16 canonical proteins from only nine genes within its 10 kb genome. Expression of the structural genes , and , the regulatory genes and and the accessory genes , , and enables assembly of the viral particle, regulates viral gene transcription, and equips the virus to evade or counteract host immune responses. In addition to the canonically expressed proteins, a growing number of publications describe the existence of non-canonical fusion proteins in HIV-1 infected cells. Most of them are encoded by the -- locus. While the majority of these fusion proteins (e.g., TNV/p28 , p18, Tat1-Rev2, Tat^8c, p17, or Ref) are the result of alternative splicing events, Tat-T/Vpt is produced upon programmed ribosomal frameshifting, and a Rev1-Vpu fusion protein is expressed due to a nucleotide polymorphism that is unique to certain HIV-1 clade A and C strains. A better understanding of the expression and activity of these non-canonical viral proteins will help to dissect their potential role in viral replication and reveal how HIV-1 optimized the coding potential of its genes. The goal of this review is to provide an overview of previously described HIV-1 fusion proteins and to summarize our current knowledge of their expression patterns and putative functions.
PubMed: 28119676
DOI: 10.3389/fmicb.2016.02152 -
Cells Jul 2022Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct...
Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis.
Topics: Animals; Autophagy; Beclin-1; DNA, Mitochondrial; Homeostasis; Mice; Mitochondria; Myocardial Infarction; Myocardial Reperfusion Injury; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley
PubMed: 35805195
DOI: 10.3390/cells11132111 -
Biochimica Et Biophysica Acta Mar 2016Cyanobacteria exhibit a complex form of membrane differentiation that sets them apart from most bacteria. Many processes take place in the plasma membrane, but... (Review)
Review
Cyanobacteria exhibit a complex form of membrane differentiation that sets them apart from most bacteria. Many processes take place in the plasma membrane, but photosynthetic light capture, electron transport and ATP synthesis take place in an abundant internal thylakoid membrane. This review considers how this system of subcellular compartmentalisation is maintained, and how proteins are directed towards the various subcompartments--specifically the plasma membrane, periplasm, thylakoid membrane and thylakoid lumen. The involvement of Sec-, Tat- and signal recognition particle- (SRP)-dependent protein targeting pathways is discussed, together with the possible involvement of a so-called 'spontaneous' pathway for the insertion of membrane proteins, previously characterised for chloroplast thylakoid membrane proteins. An intriguing aspect of cyanobacterial cell biology is that most contain only a single set of genes encoding Sec, Tat and SRP components, yet the proteomes of the plasma and thylakoid membranes are very different. The implications for protein sorting mechanisms are considered. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Prof Conrad Mullineaux.
Topics: Bacterial Proteins; Cyanobacteria; Protein Transport; Thylakoids
PubMed: 26341016
DOI: 10.1016/j.bbabio.2015.08.010 -
AIDS Research and Therapy Sep 2023Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag,... (Review)
Review
Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research.
Topics: Humans; HIV-1; Tumor Suppressor Protein p53; HIV Infections; China; Genes, Viral
PubMed: 37691100
DOI: 10.1186/s12981-023-00563-7 -
Orphanet Journal of Rare Diseases Dec 2022Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by... (Review)
Review
BACKGROUND
Different types of non-hepatorenal tyrosinemia are among the rare forms of tyrosinemia. Tyrosinemia type II and III are autosomal recessive disorders caused by pathogenic variants in the tyrosine aminotransferase (TAT), and 4-hydroxyphenyl-pyruvate dioxygenas (HPPD) genes, respectively. There are still unclarified aspects in their clinical presentations, mutational spectrum, and genotype-phenotype correlation.
MAIN BODY
In this study, we evaluated the spectrum of TAT and HHPD gene mutations in patients with tyrosinemia type II and III. Moreover, biochemical and clinical findings are evaluated to establish a genotype-phenotype relationship in the above-mentioned patients. Thirty-three TAT variants have been reported in 42 families, consisting of 21 missense variants, 5 frameshift variants, 4 nonsense variants, 2 variants that primarily cause splicing site, and 1 skipping complete exon (large deletion). The most common variant is p.Arg57Ter, causing a splicing defect, and resulting in premature termination of translation, which was found in 10 patients from 3 families. In HPPD gene, eleven variants in 16 patients have been reported including 7 missense variants, 2 nonsense variants, 1 splice defect, and 1 frameshift variant so far. All variants are unique, except for p.Tyr160Cys, which is a missense variant found in two different patients. Regarding genotype-phenotype correlations, in 90% of tyrosinemia type II patients, positive clinical and biochemical correlations with a detected variant are observed. In HPPD gene, due to the small number of patients, it is not possible to make a definite conclusion.
CONCLUSION
This is the first large review of variants in TAT and HPPD, highlighting the wide spectrum of disease-causing mutations. Such information is beneficial for the establishment of a privileged mutation screening process in a specific region or ethnic group.
Topics: Humans; Ethnicity; Exons; Mutation; Mutation, Missense; Tyrosinemias
PubMed: 36471409
DOI: 10.1186/s13023-022-02579-0 -
Epigenomics Mar 2022To understand the effect of HIV infection and cocaine exposure on piRNA expression in human primary astrocytes. We used small RNA sequencing analysis to investigate...
To understand the effect of HIV infection and cocaine exposure on piRNA expression in human primary astrocytes. We used small RNA sequencing analysis to investigate the impacts of HIV-1 Tat and cocaine coexposure on the expression of piRNAs in human primary astrocytes. We identified 27,700 piRNAs and analyzed them by small RNA next-generation sequencing. A total of 239 piRNAs were significantly altered by HIV-1 Tat and cocaine coexposure. We also identified PIWIL1, PIWIL2, PIWIL3 and PIWIL4 as interacting partners of piRNAs that were affected by cocaine and HIV-1 Tat coexposure. Epigenetic changes in the expression levels of these piRNA targets were associated with Kyoto Encyclopedia of Genes and Genomes pathways of energy metabolism and neurodegeneration. These findings provide evidence that cocaine exposure and HIV infection affect the expression levels of piRNA, PIWIL1, PIWIL2, PIWIL3 and PIWIL4.
Topics: Argonaute Proteins; Astrocytes; Cocaine; Energy Metabolism; HIV Infections; HIV-1; Humans; RNA, Small Interfering
PubMed: 35170353
DOI: 10.2217/epi-2021-0252 -
Biomedicines Aug 2018Acting at a cell surface receptor on the extracellular domain of integrin αvβ3, thyroid hormone analogues regulate downstream the expression of a large panel of genes... (Review)
Review
Acting at a cell surface receptor on the extracellular domain of integrin αvβ3, thyroid hormone analogues regulate downstream the expression of a large panel of genes relevant to cancer cell proliferation, to cancer cell survival pathways, and to tumor-linked angiogenesis. Because αvβ3 is involved in the cancer cell metastatic process, we examine here the possibility that thyroid hormone as l-thyroxine (T4) and the thyroid hormone antagonist, tetraiodothyroacetic acid (tetrac), may respectively promote and inhibit metastasis. Actions of T4 and tetrac that are relevant to cancer metastasis include the multitude of synergistic effects on molecular levels such as expression of matrix metalloproteinase genes, angiogenesis support genes, receptor tyrosine kinase (/) genes, specific microRNAs, the epithelial⁻mesenchymal transition (EMT) process; and on the cellular level are exemplified by effects on macrophages. We conclude that the thyroid hormone-αvβ3 interaction is mechanistically linked to cancer metastasis and that modified tetrac molecules have antimetastatic activity with feasible therapeutic potential.
PubMed: 30135398
DOI: 10.3390/biomedicines6030089